Studies indicate that methamphetamine (METH) abuse can exacerbate neuronal damage associated with HIV/NeuroAIDS (HIV). Although the exact neurodegenerative mechanisms are unclear, neuroimaging studies reflect complex interactions affecting brain structure and function. Brain spectroscopy and morphometry studies indicate that HIV and METH can result in both additive and opposing effects, resulting in regionally-specific increases and decreases in volume. Functional neuroimaging studies (FMRI) suggest that HIV and METH contribute to unique patterns of blood oxygenation level dependent (BOLD) changes resulting in region-specific activation that vary by task. HIV infection and METH are similar, in their association with white matter abnormalities. Imaging modalities that measure white matter integrity, like diffusion tensor imaging (DTI), could explain HIV/METH-related interactions that influence alterations in brain structure and function. A NIDA program project is currently examining the links between brain morphometry and task-related BOLD activation in METH and HIV co-morbidity ("NeuroAIDS: Effects of Methamphetamine and HCV," at UCSD HIV Neurobehavioral Research Center). We propose to extend those findings by integrating DTI data that was collected on a subgroup of fifty participants representing four groups of the original cohort [HIV, METH, dually-affected (HIV+/METH+), and healthy controls (HC)]. The central aim of this proposal is to clarify the complex interaction of METH and HIV effects by applying new measures of white matter integrity to existing SMRI and FMRI data. Regional brain morphometry measures will guide identification of anatomical regions of interest (ROI) at the lobar level (i.e. parietal white matter), and at the level of specific neural subdivisions (caudate nucleus, lateral prefrontal cortex). Using these ROIs, we will identify group differences in diffusion tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD) at three levels: in global white matter, within specific regions of white matter identified as abnormal with SMRI, and within specific white matter regions of interest. DTI metrics will also provide information about the role of white matter dysfunction in SMRI patterns of atrophy and hypertrophy associated with HIV and METH. The role of white matter connectivity in brain function will be investigated by evaluating white matter integrity in regions adjacent to areas of significant task- related BOLD activation associated with neuromotor and neurocognitive abnormalities. Finally, we will investigate associations between DTI indices and biologic markers of immune response, drug use history, and overall neurocognitive impairment in these groups. PUBLIC HEALTH RELEVANCE: This R03 study would integrate diffusion tensor imaging with structural and functional imaging data to explore the role of white matter connectivity in neurocognitive deficits related to HIV and methamphetamine co-morbidity. These findings could illustrate how white matter integrity mediates the relationships between regional alterations in brain structures and measures of brain functioning.